An overview of pharmacological effects of Crocus sativous and its constituents

Crocus sativus L. was used for the treatment of a wide range of disorders in traditional medicine. Due to the extensive protective and treatment properties of C. sativus and its constituents in various diseases, the purpose of this review is to collect a summary of its effects, on experimental studies, both in vitro and in vivo. Databases such as PubMed, Science Direct, and Scopus were explored until January 2023 by employing suitable keywords. Several investigations have indicated that the therapeutic properties of C. sativus may be due to its anti-oxidant and anti-inflammatory effects on the nervous, cardiovascular, immune, and respiratory systems. Further research has shown that its petals also have anticonvulsant properties. Pharmacological studies have shown that crocetin and safranal have anti-oxidant properties and through inhibiting the release of free radicals lead to the prevention of disorders such as tumor cell proliferation, atherosclerosis, hepatotoxicity, bladder toxicity, and ethanol induced hippocampal disorders. Numerous studies have been performed on the effect of C. sativus and its constituents in laboratory animal models under in vitro and in vivo conditions on various disorders. This is necessary but not enough and more clinical trials are needed to investigate unknown aspects of the therapeutic properties of C. sativus and its main constituents in different disorders.


Introduction
The utilization of Crocus sativus L. dates back to a period of 3500 years.In the nation of Iran, the expanse dedicated to the cultivation of C. sativus amounts to approximately 1.64 million square kilometers (1,2).C. sativus was extensively utilized in Asia as a potent medicinal herb in the management of coronary artery disease, hypertension, gastrointestinal ailments, irregularities in the menstrual cycle, and impairments in memory and cognitive function.Furthermore, it serves as a widely employed spice in the culinary industry.A multitude of investigations have indicated that the therapeutic attributes of C. sativus may be attributed to its anti-oxidant and anti-inflammatory effects on the nervous, cardiovascular, immune, and respiratory systems.Both animal and human studies on C. sativus extract have evidenced that this botanical specimen exhibits anticonvulsant and anti-Alzheimer properties (3,4).For a long time in ancient Iran, Egypt, and Europe, C. sativus was used as a medicinal plant in the treatment of back pain, diabetes, and measles.Other uses of the plant include treatment for pre-eclampsia, abscesses, and wound healing.Today, modern research studies have shown that C. sativus compounds have healing properties, including anti-cancer, anti-diabetic, and analgesic activities.It also prevents renal ischemia and enlarged liver and spleen, as well as relaxing smooth muscles (5).
Due to the extensive protective and therapeutic properties of C. sativus and its constituents in various diseases, the purpose of this review is to collect a summary of various pharmacological properties of C. sativus and its constituents, in both in vitro and in vivo experimental studies.

Usage in traditional medicine
The history of C. sativus cultivation dates back centuries and is now cultivated in countries such as Iran, India, Spain, Greece, and Turkiye.The demand for C. sativus cultivation has increased due to its widespread pharmacology leading to the widespread cultivation of C. sativus around the world (6).C. sativus cultivation has been increasing for many years due to its late fruiting as well as the difficulty of cultivating it, and its crop has even been abandoned in many countries of the world.At present, traditional cultivation methods have been replaced by mechanized and machine methods, and there are no restrictions on the collection of this crop (7,8).
In Iranian medical books, C. sativus is introduced as a hot and dry spice (9), and its properties are introduced with the words "Moder", "Moghavi", "Mohalel", "Molatef ", and "Monaghi", which mean tonic, resolvent, attenuant, and abstergent, respectively (10).Many studies have shown that C. sativus and its active constituents have extensive bioactivity and pharmacological properties.The traditional uses of C. sativus in ancient times are summarized in Table 1.
Today in the world, there is a strong tendency to use medicinal plants to treat diseases.This tendency is due to the high cost and side effects of industrial drugs on several illnesses and not exactly necessarily because herbal medicines are more effective on diseases (2).In addition to therapeutic uses, in ancient Iran, C. sativus with gold, flowers, and sweets was used in celebrations.It's also the most important compound in the most powerful drugs of the past and has been used as an anti-inflammatory drug in cough, sore throat, cold swellings, otitis, and wounds (11).
Between the 13th and 18th centuries, the main source of medical education in the West was the Qanoon Felteb and Kitab al-Hawi books, written by Avicenna and Rhazes, respectively (12).In ancient India, having a lot of C. sativus was a sign of wealth and royalty.Homemade remedies, herbal formulations, anti-poisonous, and Ayurvedic medicine were recommended for the applications of C. sativus (13).In Indian Ayurvedic medicine literature, C. sativus was introduced as an adaptogen.Other properties of this plant are cardiac tonic, nervine tonic, livotonic, diaphoretic, diuretic, carminative, emmenagogue, lactogogue, febrifuge, stimulant, relaxant, sedative, antistress, and anti-anxiety (14).C. sativus has also been used to revitalize facial skin, cleanse the liver of bile, treat cough, heal diaphragmitis, and as a substance to reduce eye inflammation in ancient Rome (15).
The Romans also used C. sativus to treat jaundice and to clear bile (16).Historical documents show that C. sativus was first cultivated during the reign of the Media in parts of the Zagros and Alvand Mountains (17).Razi stated that the use of C. sativus due to euphoria leads to a psychotic state (18).C. sativus has traditionally been prescribed to maintain lung tone, improve respiratory function, and treat asthma.It also protects the cardiovascular system, improves cardiovascular function, and treats heart palpitations by maintaining heart tone.In addition to enhancing blood circulation and providing appropriate nourishment to the cardiac organ, C. sativus also exhibits antithrombotic and thrombolytic properties.This plant is known as a strong liver protector and prevents liver blockage in the Gastrohepatic system.Tabari identifies properties such as hotness, moderateness, dryness, water solubility, and bitterness for C. sativus and believes that these properties can be effective in treating liver obstruction (19).

Method
In this comprehensive review, the keywords including "Crocus sativus", "Saffron", "safranal", "crocin" "crocetin", "cancer", "cardiovascular", "gastrointestinal", "renal" and "metabolic disorders" were searched in the popular search engines and databases including Iran Medex, Google Scholar, Medline, Pubmed, Scopus, and Wiley Online Library until the end of January 2023 to identify articles that explain numerous experimental effects of C. sativus and its main constituents on various diseases.

Anti-cancer effect C. sativus
The ethanolic extract derived from the plant C. sativus has the potential to exert a fatal impact on human hepatocellular carcinoma cells (HepG2) as well as human cervical carcinoma cells (HeLa), primarily through the induction of apoptosis.This extract effectively eliminates tumor cells without causing any adverse effects on normal cells (24).The aqueous extract of C. sativus demonstrates the capability to induce intoxication in both hepatocellular carcinoma (hepg-2) and laryngeal carcinoma (Hep-2) cell lines through its ability to restrict the production of nitric oxide (NO) (25).
Treatment with C. sativus in human pancreatic cancer cell lines (bxpc-3) and other cancer cells resulted in the initiation of apoptosis via G1-phase cell cycle arrest of bxpc-3 cells and consequently diminished tumor progression (26).
The administration of an aqueous extract derived from C. sativus to both human transitional cell carcinoma (TCC) and mouse non-neoplastic fibroblast cell lines demonstrated a notable suppression of cellular division and proliferation (27).
Consuming an aqueous extract of C. sativus (100 to 800 μg/ml) in human breast carcinoma cells showed inhibitory effects on matrix metalloproteinase gene expression dosedependently which was highest at its concentration of 200 μg/ml (28).
The extract obtained from Zhejiang C. sativus has exhibited notable anti-proliferative and pro-apoptotic properties.This has been observed through the modulation of cell proliferation activity and induction of apoptosis in human non-small cell (A549) and small cell lung cancer cell lines (H446) in vivo.Moreover, the administration of C. sativus extract (at a dosage of 100 mg/kg, orally for a duration of 28 days) has been found to induce cell apoptosis, resulting in a reduction in xenograft tumor size.This effect is attributed to the activation of caspase-3, -8, and -9 pathways (29).
Treatment using an extract derived from C. sativus, as well as the compounds crocin and crocetin, exhibited the ability to reduce tumor growth in male mice afflicted with prostate cancer, specifically the PC3 and 22rv1 cell lines.This reduction was achieved through the downregulation of N-cadherin and beta-catenin, coupled with an increase in E-cadherin expression.Consequently, this process effectively suppressed the occurrence of epithelialmesenchymal transition (EMT).Moreover, the inhibition of prostate cancer cell invasion and migration was attributed to the decreased expression and activity of metalloproteinase and urokinase.Remarkably, the antitumor effects of crocetin surpassed those exhibited by the other two compounds (30).
C. sativus can be used as an anti-cancer agent in two ways, inhibition of the cell cycle by targeting the DNA sequence and modulating gene expression, which leads to cessation of cell proliferation in the early stages, and activation of apoptosis, which leads to the death of cancer cells.In diethyl nitrosamine (DEN)-induced liver cancer in rats, C. sativus treatment through these two methods led to chemopreventive action against liver cancer cells.DEN led to the formation of structures called hepatic dyschromatic nodules in the liver tissue but in contrast, C. sativus reduced it.Based on these observations, C. sativus has hepatoprotective effects in liver cancer through the induction of apoptosis, inhibition of cell proliferation, and inflammatory and anti-oxidant activities (31).
Topical use of aqueous extract of C. sativus (100 mg/ kg) reduced skin carcinogenesis, and methylchloanthrene (MCA) induced soft tissue sarcomas in mice through inhibition of apoptosis induction (32).In addition, the plant modulated inflammatory response and inhibited oxidative damage in DEN-induced hepatic cancer (31).
The formation of papillomas in female Swiss albino mice with skin carcinogenesis induced by dimethyl benz[a] anthracin (DMBA) was hindered by the administration of an aqueous infusion of C. sativus (50-500 mg/kg).This hindrance was achieved by altering the activity of phase II detoxifying enzymes, namely glutathione peroxidase (GPX), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) (33).
Consuming an aqueous extract of C. sativus as a daily supplement in the kidney cancer model led to a reduction in the oxidative effects of chemotherapy due to cisplatin, and reduced renal excretion (34).In cisplatin-, mitomycin-Cand urethane-induced mice chromosomal damage, pretreatment with dried stigmas of C. sativus (25, 50, and 100 mg/kg), spatially high doses of C. sativus, significantly reduced the genotoxicity of this genotoxin.However, all three doses showed a protective effect against urethane (35).Pre-treatment with aqueous extract of C. sativus reduced the side effects of drugs genotoxicity (cisplatin, urethane, cyclophosphamide, and mitomycin-C) and decreased their oxidative effects.Therefore, it can play a moderating role in peroxidation and detoxification caused by chemotherapy (36).

Crocin
The inhibitory properties of crocin have been demonstrated through the utilization of the MTS assay in three distinct cell lines, namely HCT-116, SW-480, and HT-29.It is important to note that these effects were observed exclusively in cancerous cells, as non-cancerous cells remained unaffected (37).Crocin increased the Bax/ Bcl-2 ratio to induce apoptosis, and tumor proliferation and growth (38).Administration of 250 and 500 μg/kg crocin after melanoma lung metastasis implantation, decreased uronic acid, hexosamine, hydroxyproline, gamma-glutamyl transpeptidase (g-GGT), and serum sialic acid, which were metastasis-induced biomarkers, and crocin prevented the expression of genes such as vascular endothelial growth factor (VEGF), ERK-2, matrix metalloproteinase (MMP)-2, MMP-9, and K-ras (39).
In the experimental model of colorectal cancer in animals induced by rat adenocarcinoma DHD/K12-prob cells, prolonged administration of crocin resulted in a reduction in tumor growth and an increase in survival time (40).Crocin was subjected to testing on both animal and human colon adenocarcinoma cells (DHD/K12-prob and HT-29), demonstrating a significant cytotoxic effect on these cells, leading to the eradication of cancer cells and a decrease in tumor growth (40).Moreover, the utilization of pegylated nanoliposomes containing crocin resulted in cytotoxicity against colon carcinoma (C-26) cells in laboratory settings (41).
Crocin was found to induce inhibition of the cell cycle progression and apoptosis in breast cancer tumors through the down-regulation of cyclin D1 and p21Cip1 expression (42).The combined administration of crocin and crocetin in mice with breast cancer led to a reduction in the growth of cancerous tumors, except that crocin had a greater protective effect in the early stages of tumor growth (43).

Crocetin
Crocetin, trans-crocin-4, and safranal exhibit remarkable efficacy in impeding the proliferation of breast cancer cell tumor lines, namely MDAMB-231 and MCF-7, whilst simultaneously manifesting anti-proliferative attributes against breast cancer cells (44).The co-administration of crocin alongside gamma radiation or paclitaxel therapy instigated apoptosis and engendered a synergistic impact on reducing the survival rate in MCF-7 breast cancer cells (45).
In both in vivo (50, 100, 200 µM/L) and in vitro (4 mg/kg, for 30 days) studies, crocetin exhibited inhibitory effects on cell proliferation in pancreatic cancer cells by significantly modifying the expression of Cdc-2, Cdc-25C, Cyclin-B1, and epidermal growth factor receptor.Moreover, crocetin also reduced the proliferation process and H3-thymidine incorporation in various cancer cells such as BxPC-3, Capan-1, and ASPC-1.Additionally, it induced apoptosis through the modulation of the Bax/Bcl-2 ratio (38).Crocetin effectively suppressed the proliferation and invasiveness of highly invasive breast cancer cells by down-regulating the expression of matrix metalloproteinases in MDA-MB-231 cells (46).
Injection of crocetin in a lung cancer model induced by benzopyrene in Swiss albino mice resulted in a reduction of cell proliferation by 45% and 68% after 8 and 18 weeks of treatment, respectively.The crocetin compound exhibited both preventive and therapeutic effects on benzopyreneinduced lung cancer in the animal model, demonstrating its potential as an anticarcinogenic agent.These effects were attributed to the inhibitory impact of crocetin on polyamine synthesis and alterations in glycoprotein levels in lung cancer (47).Furthermore, crocetin demonstrated the ability to suppress cell proliferation by inhibiting glycoprotein and polyamine synthesis, thereby affecting proliferating cells (47).
Administration of crocetin (20 mg/kg) as a pretreatment before and after induction of lung cancer by Benzo(a) pyrene B(a)p (50 mg/kg, orally) in mice showed its anti-tumor activity through increasing activity of anti-oxidants and glutathione metabolizing enzymes in both liver and lung mice tissue (48).Treatment with crocetin after the initiation of colitis by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) resulted in a reduction in the levels of malondialdehyde (MDA), the expression of TH1 and TH2 cytokines, and inducible NO synthase due to the down-regulation of nuclear factor kappa B (NF-κB).These alterations consequently hindered the occurrence of colorectal cancer induced by colitis using the regulation of specific proteins (49).

Safranal
Safranal can be considered an anti-cancer agent by preventing gene toxicity.This substance can protect against DNA damage caused by Methyl methane sulfonate (MMS) (52).Table 3 presents a summary of the anti-cancer properties exhibited by C. sativus and its constituents.
The application of hydroalcoholic extract derived from C. sativus at a dosage of 200 mg/kg to hypertensive rats induced with NG-nitro-L-arginine methyl ester (L-NAME) yielded a reduction in cross-section area, media thickness, and elastic lamellae number.Additionally, a decrease in hypertension was observed (56).A recent investigation has demonstrated that the introduction of C. sativus extract, achieved using stimulation and subsequent production of NO, results in the fortification of the atrioventricular node's (AV node) protective function against supraventricular arrhythmia in rabbits (57).Administration of an aqueous extract of C. sativus at varying doses (10, 20, and 40 mg/ kg, IP) over a period of 5 weeks resulted in a reduction of mean systolic blood pressure (MSBP) in a dose-dependent manner in acid desoxycorticosterone acetate (DOCA)induced hypertensive rats (58).
Intravenous (IV) injection of aqueous extract of C. sativus stigma (2.5, 5, and 10 mg/kg), crocin, and safranal reduced hypertension in normotensive and hypertensive anesthetized rats without activating tachycardia reflex.Although all three compounds improved heart function and reduced vasoconstriction, safranal had a stronger hypotensive effect on lowering blood pressure than the other two compounds.In contrast, in anesthetized rats, crocin had a stronger antihypertensive effect (59).

Crocin
Intraperitoneal (IP) daily injection of crocin for three weeks improved arrhythmia which is followed by reperfusion.Heart IR led to a decrease in anti-oxidant agents such as SOD and glutathione (GSH) activities and an increase in MDA levels in the heart muscle.Treatment with crocin increased CAT activity by modulating all of these factors (60).Oral consumption of crocin (40 mg/kg) for 21 days showed the same effects as vitamin E, against oxidative injury in the treatment of cardiac I/R injury (61).Administration of crocin to three animal groups with 10, 20, and 40 mg/kg doses, showed cardiac protective effects against post-I/R after infarction.In the same study, coadministration of the highest dose of crocin (40 mg/kg) with vitamin E (100 mg/kg) reduced the size of myocardial infarction and improved the dynamic parameters (61).In bovine aortic endothelial cells, crocin increased the bcl-2/ bax ratio and expression and inhibited aortic endothelial cell apoptosis and atherosclerosis (62).
In hypertensive rats induced by DOCA-salt, the administration of crocin (50, 100, and 200 mg/kg, IP) over a period of 5 weeks resulted in a dose-dependent reduction in mean systolic blood pressure (MSBP) (58).In addition, crocin reversed the systolic blood pressure and heart rate in diazinon (DZN)-induced hypotension in rats (63).In animal models of hemorrhagic shock, IV injection of crocin (60 mg/kg) in the initial stages of resuscitation in mice, increased arterial PO2 and decreased PCO2.This action led to a reduction in MDA, TNF-α, and IL-6 serum levels and increased IL-10.It also prevented NF-kb pathway activation.These processes ultimately protect the lungs from tissue damage caused by ischemia (64).
In a separate investigation employing an identical protocol, the administration of crocin (at a dosage of 60 mg/kg) was intravenously introduced into the animal subsequent to the induction of hemorrhagic shock through blood withdrawal.The findings indicated a reduction in tissue damage in various organs, including the kidney, liver, pancreas, and muscle, as a result of crocin administration.This phenomenon occurs using the restriction of the activation of the NF-κB pathway in lung tissue, the inhibition of serum concentrations of the proinflammatory cytokines TNF-α and IL-6, and an elevation in the level of the antiinflammatory cytokine IL-10.Collectively, these effects have the potential to mitigate the deleterious consequences associated with the release of tissue inflammatory factors during episodes of hemorrhagic shock (64).

Crocetin
In the context of atherosclerosis in rats induced by a high cholesterol diet (HCD), the administration of crocetin at dosages ranging from 25 to 50 mg/kg over 10 weeks exhibited beneficial effects on the lipid profile as well as other inflammatory mediators.Crocetin also augmented lipid profile toward standard value, and coadministration of crocetin with simvastatin certificated dyslipidemia, through increased anti-oxidant activity and inhibition of phosphorylated p38 mitogen-activated protein kinase (MAPK) (65).Crocetin inhibited the proliferation of vascular smooth muscle cells (VSMs) exposed to the angiotensin enzymes (ages) and also reduced the levels of inflammatory factors such as TNF-α and IL-6, and structural enzymes such as MMP-2 and MMP-9.These effects led to cardiovascular protection against the complications of diabetes (66).
Vascular permeability in fibroblasts and human umbilical vein endothelial cells (HUVECs) is controlled by cadherin which is a key protein that controls the permeability of these

cells. Crocetin treatment increased vascular endothelialcadherin expression in tissues and suppressed cellular inflammatory infiltration (69). Crocetin reduced VEGFinduced tube formation by HUVECs and migration of HRMECs, p38 and protected VE-cadherin (70).
In an experimental rat model of IR, administration of crocetin (at a dose of 50 mg/kg) resulted in a decrease in cardiac damage, oxidative stress, and inflammation.This was evidenced by a reduction in the size of the infarct, levels of creatine kinase-MB (CK-MB), MDA, and TNF-α, as well as an increase in the activity of total SOD and the antiinflammatory cytokine IL-10 (71).
Crocetin (25 and 50 mg/kg, IP, for 15 days) treatment on norepinephrine-induced cardiac hypertrophy, significantly improved myocardial function compared to captopril as a standard drug through increased SOD and GPX activities and decreased lipid peroxidation in the cardiac myocytes.However, captopril showed a stronger effect on left ventricular index improvement (72).The administration of crocetin demonstrated an augmentation in the functionality of voltage-dependent pumps, including Na/K-ATPase in cardiac cells and Ca2/Mg2-ATPase in mitochondria.Additionally, there was a notable decrease observed in the expression of MMP-2 and MMP-9 mRNA.Crocetin inhibited energy metabolism disruption in noradrenalineinduced apoptosis in cardiac myocytes through increased mitochondrial membrane potential due to activation of Na/K ATPase and Ca ATPase pumps as well as induction of mitochondrial succinic dehydrogenase activity (73).
Administration of crocetin (50 mg/kg, thrice daily over a duration of one week) to adult male C57/B6 mice with cardiac hypertrophy induced by aortic banding (AB) not only improved hypertrophy but also reversed the course of the injury.The observed impacts were a result of the inhibition of the reactive oxygen species (ROS)-dependent MAPK/extracellular signal-regulated kinase-1/2 (ERK1/2) pathway and stimulation of GATA binding protein 4 (GATA-4) activation.At the molecular level, crocetin inhibited hypertrophy by blocking NF-κB signaling (74).
Treatment of LDL-induced atherosclerosis in rabbits with crocetin in both in vivo and in vitro conditions increased endothelial NO synthase (eNOS) activity in aortic endothelial cells due to enhancement of NO production.This compound is also capable of relaxing the thoracic aorta (75).One of the major growth factors that plays a key role in the proliferation of VSMCs is angiotensin II (Ang II), which is produced as a result of the activation of the reninangiotensin system.The studies indicated that crocetin suppresses Ang II-induced VSMC proliferation via inhibited phosphorylation, activation, and nuclear translocation of extracellular signal-regulated kinase1/2 (ERK1/2) (76).
Treatment with crocetin on bovine aortic VSMCs induced by Ang II effectively obstructed the progression of the cell cycle initiated by Ang II, thus halting the cells in the G0/G1 phase.This modification hindered the activation of extracellular signal-regulated kinase1/2 (ERK1/2) and the subsequent expression of its downstream effector c-fos, which were initially stimulated by Ang II.Furthermore, it enhanced the activity of SOD and led to a decrease in intracellular ROS (69).
Safranal treatment (0.1-0.5 ml/kg/day, IP) for two weeks in IR-heart induced by occluded left anterior descending coronary artery, resulted in enhanced left ventricular functionalities and decreased infarct size, plausibly using Akt/GSK-3b (glycogen synthase kinase)/eNOS pathway phosphorylation and the suppression of IKK-b/nfқb protein expression in cardiac cells.In addition, safranal modulated the cardiac injury indicators such as lactate dehydrogenase (LDH) and CK-MB as well as reducing TNF-α levels, inflammatory cells, edema, and enhanced hemodynamic heart parameters.Therefore, safranal preserves the myocardial architecture of the heart (78).Table 4 presents a summary of the cardiovascular effects exhibited by C. sativus and its constituents.

Anti-depressant effect C. sativus
Administration of aqueous (160 and 320 mg/kg) and alcoholic (200 and 800 mg) extracts of C. sativus and its constituents improved depressive symptoms in depressed mice and showed better results than fluoxetine.In addition, the results showed more therapeutic potency and inactive time reduction compared to the control group (79).The antidepressant effect, resulting from an augmentation in climbing time and stereotypic activity, was likewise observed following the administration of aqueous and ethanolic extracts of C. sativus in mice (80).Treatment with the petal and ethanolic extracts of C. sativus, crocin, and safranal led to treatment of depression in mice (81).Clinical trials confirmed that C. sativus petals similar to fluoxetine can treat mild to moderate depression (82,83).

Crocin and Safranal
Administration of crocin (50-600 ml/kg) and safranal (0.5 mg/kg) showed antidepressant activity using a forced swimming test in depressed mice (79).Table 5 presents a summary of the neuroprotective effects exhibited by C. sativus and its constituents.

Anti-seizure effect C. sativus
In pentylenetetrazole (PTZ)-induced seizure animals models, the aqueous (0.08, 0.32, 0.56 and 0.80 g/kg, IP) and ethanolic (0.2-2.0 g/kg, IP) extracts of C. sativus reduced convulsant activity, onset of tonic convulsions, period of seizure using maximal electroshock seizure (MES) tests, and mortality in epileptic mice.At the dosage of 80 mg/kg, the aqueous extract exhibited a comparable efficacy to that of 10 mg/kg of phenobarbital in the animal models of PTZinduced seizures (84).Both the aqueous (200, 400, and 800 mg/kg, IP) as well as the ethanolic (250 and 500 mg/kg, IP) extracts of C. sativus also yielded a noteworthy decrease in convulsion activity in rats with PTZ-induced seizures (85).

Safranal
Safranal (0.15 and 0.35 ml/kg, IP) reduced the duration of seizures and could be a protective agent against animal death in PTZ-induced convulsions in mice (87).Safranal (72.75, 145.5, and 291 mg/kg) exhibited a diminishing effect on the occurrence of minimal clonic and generalized tonic-clonic seizures in PTZ-induced seizure mice.This effect was found to be reliant on the dosage administered and occurred through the mechanism of interaction with the GABAA-benzodiazepine receptor (88).A single dose of safranal (291mg/kg, IP) showed an antiepileptic effect in acute epileptic laboratory animal models via modulating GABA receptors (89).Administration of safranal showed antiabsence seizure activity in epileptic C57BL/6 mice via modulating benzodiazepine binding sites of the GABAA receptor complex (89).Table 5

Pharmacological effects of Crocus sativous
Saadat et al.

Neuroprotective effects C. sativus
In the context of experimental autoimmune encephalomyelitis (EAE) mice, administration of an ethanolic extract derived from C. sativus led to a noteworthy mitigation of leukocyte infiltration within the spinal cord.Furthermore, this treatment exhibited a decline in clinical manifestations associated with EAE in C57BL/6 mice (90).In the context of rat experiments involving middle cerebral artery occlusion (MCAO), the administration of C. sativus extract prior to the onset of cerebral ischemia exhibited a significant impact.This impact was observed through the modulation of cerebral MDA, GPX, SOD, and CAT, as well as the regulation of glutamate and aspartate levels and the activity of Na+/K+ ATPase.These findings serve to Continued Table 5.   CCINP: chronic constriction injury model of neuropathic pain, EAE: experimental autoimmune encephalomyelitis, ERK1/2: extracellular signal-regulated kinase1/2, ext.: extract, HSP: hippocampal synaptic plasticity, INPP4: inositol polyphosphate 4-phosphatase, LTP: long-term potentiation, MCAO: middle cerebral artery occlusion, MHNR: mediated hippocampal neurons responses, MWM: Morris water maze, NMDA: N-methyl-D-aspartate, NPA: nitropropionic acid, NSS: neurological severity score, PDRSM: performance deficits in the recognition and spatial memory, PTZ: pentylenetetrazole, ROS: reactive oxygen species, SCC: spinal cord contusion, SLM: spatial learning and memory, SMD: spatial memory deficit, SOD: superoxide dismutase, SP: synaptic proteins, STZ: streptozotocin, VSMC: vascular smooth muscle cell demonstrate the protective properties of C. sativus stigma aqueous extract (100 mg/kg, PO) by means of inhibiting peroxidation and reducing glutathione levels and other anti-oxidant agents.The ultimate goal of these actions is to prevent neuronal cell death resulting from ischemic conditions (91).In neurodegenerative disorders such as Alzheimer's and Parkinson's, the extracts derived from the stigmas of C. sativus effectively impeded the formation of amyloid fibrils, displaying a concentration-and timedependent manner (92).
C. sativus extract (60 mg/kg) inhibited the memory loss processes in streptozocin (STZ)-induced Alzheimer rats (93).Administration of ethanolic extract of C. sativus and crocin in Alzheimer patients resulted in healing of Aβ brain pathology and decreased neuro-inflammation through increased blood-brain barrier of amyloid-β and apolipoprotein E (apoE), as well as degradation of related enzymes (94).Ethanolic extract of C. sativus (125 and 250 mg/kg, PO) on hippocampus dentate gyrus in anesthetized rats, reduced the ethanol-induced long-term potentiation (LTP)-blockade and in higher dose (500 mg/kg, PO) reversed ethanol-induced impairment in brain direct ethanol injection.The ethanolic extract also improved synaptic plasticity in the hippocampus through direct action on the CNS and peripheral function (95).
Neuropathic pain in the experimental animal model was attenuated by aqueous and ethanolic extracts of C. sativus (50, 100, and 200 mg/kg) and safranal (0.025, 0.05, and 0.1 mg/kg), and behavioral symptoms were improved (96).Suppression of oxidative stress, modulation of proinflammatory cytokines, and apoptosis attenuation are also the results of administration of aqueous and ethanolic extracts of C. sativus (200 mg/kg, IP) (97).Using passive avoidance tasks and object recognition, it was shown that C. sativus extract (SE at 30 and 60 mg/kg) can store and retrieve information and reduce side effects of scopolamine administration such as spatial memory disorder.Administration of the plant extract with crocins (30 mg/kg, and to a lesser extent, 15 mg/kg) showed similar results (98).Using the passive avoidance paradigm through the Y maze task, it was demonstrated that the aqueous extract of C. sativus (60 mg/kg, IP) as well as safranal (60 mg/kg, IP, for 3 weeks) exhibited the ability to restore cognitive abilities by enhancing learning and memory, while also counteracting the decline in cognitive function observed in rats.
Hydro-alcoholic extract of C. sativus (30 mg/kg, IP for 15 days) in amnestic mice induced by D-galactose and sodium nitrite (nano2), showed preventive and therapeutic effects in retrieval learning and memory in one-way passive and active avoidance tests (99).C. sativus hydro-ethanolic extract inhibited ketamine-induced behavioral defects by reducing extracellular glutamate levels.It also binds to NMDA receptors and inhibits the transfer of glutamate in synaptic apace in a concentration-dependent manner (100).C. sativus aqueous extract (150 and 450 mg/kg, IP, for 5 days, three days before and two days after the training phase) improved the time latency for entering the dark compartment in morphine-induced memory impairment male mice (101).C. sativus extract (10, 30, and 50 mg/kg, IP, for 5 consecutive days) also ameliorated spatial learning and memory in ethanol-induced mice and reversed the ethanolinduced hippocampal long-term weakening, and reduced side effects of morphine in a dose-dependent manner (102).
One of the notable consequences of the C. sativus extract on cognitive function is its efficacy in impeding the induction of hippocampal long-term potentiation (LTP) caused by ethanol.Administering C. sativus at a dosage of 250 mg/kg orally may prove to be efficacious in preventing the inhibition of LTP in the dentate gyrus caused by acetaldehyde (103).Using object recognition and the step-through passive avoidance task, it was shown that the extracts of C. sativus (30 and 60 g/kg, orally, 24 hr), improved memory through modulating storage and/or retrieval of information (104).C. sativus extract (1 mg/kg/day, IP) showed a protective effect against energy metabolism disorder in the 3-nitropropionic acid-induced mitochondrial toxicity (105).
Administration of C. sativus significantly improved the memory and learning of adult and aged mice in the passive avoidance paradigm by reducing anti-oxidant factors and the caspase-3 enzyme activity modulation.C. sativus (1-250 µg/ml), crocetin, and safranal (1-125 µm) reduced the toxicity induced by hydrogen peroxide in neuroblastoma SH-SY5Y cells in vitro (106).C. sativus extract and its constituents, crocetin, dimethylcrocetin, and safranal bound to the docking site of acetylcholinesterase and increased acetylcholine levels in the synaptic space in vitro (107).
C. sativus aqueous extract (200 mg/kg), as well as honey syrup, demonstrated an ability to counteract the neurodegenerative damage induced by aluminum.This was indicated by an increase in anti-oxidant activity, suggesting that the C. sativus extract may have a neuroprotective role in mitigating toxicity through the suppression of oxidative stress and an increase in the expression of anti-oxidant enzymes (108).In a similar study, the administration of C. sativus extract (60 mg/kg, IP, for 6 days) was found to suppress oxidative stress and enhance the recovery of enzyme activity, specifically monoamine oxidase and acetylcholinesterase, in the brain and cerebellum of mice with aluminum-induced impairment of learning and memory (109).Furthermore, there is evidence to suggest that a 3-week treatment involving C. sativus extract at a dosage of 30 mg/kg, IP, along with crocin at a dosage of 15-30 mg/kg, IP, exhibited a protective effect against oxidative stress as well as spatial learning deficit and memory damage induced by chronic stress in mice (110).
Treatment with two doses of C. sativus extract (5 and 10 μg/rat for 1 week) after the induction of multiple sclerosis (MS) using intra-hippocampal administration of ethidium bromide (EB) resulted not only in the amelioration of memory deterioration and enhancement of spatial learning, but also in a significant elevation in the levels of agents possessing anti-oxidant properties, products of lipid peroxidation, and activity of enzymes with anti-oxidant properties in the hippocampus of the groups that received treatment.Furthermore, following 7 consecutive days of treatment, the anti-oxidant status was reinstated to a state of normalcy (111).Thioflavine T-based fluorescence of Aβ1-40 measurement indicated that aqueous and methanolic extract of C. sativus reduced the aggregation and formation of Aβ fibril (a pathological sign of the onset of Alzheimer's disease) and thus inhibited memory impairment caused by the destruction of cholinergic neurons in the human brain in a time and concentration dependent manner (112).Furthermore, the extract of C. sativus exhibited an augmentation in the transcription of the gene encoding brain-derived neurotrophic factor (BDNF) and the subsequent synthesis of BDNF and cAMP response element binding protein (CREB) (113).C. sativus is capable of averting motor dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced elimination of dopaminergic neurons by upholding the BDNF factor within the neurons (114).

Crocin
In cultured rat brain microglial cells, crocin (20 µM) repressed microglial activation induced by LPS-induced inflammation, inhibited nitrite production, inactivated NF-κB signaling, decreased pro-inflammatory cytokines such as TNF-α and IL-1β, and induced apoptosis in the rat hippocampal tissue.These observations suggested that crocin can play a protective role against oxidative stress produced by active microglia cells in the brain (115).Crocin (20 and 10 mg/Kg) exhibited therapeutic effects on ischemia/ reperfusion (I/R) induced injury in mice by suppressing oxidant factors and modulating the ultrastructure of cortical microvascular endothelial (CMEC) cells.These findings suggest that the mechanisms underlying the therapeutic actions of crocin involve the inhibition of translocation of G-protein coupled receptor kinase 2 (GRK2) from the cytosol to the membrane, suppression of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), as well as reduction in the number of cortical microvessels and expression of MMP-9 (69).
In ethanol-induced memory retrieval deficit mice, preadministration of crocin (50 to 200mg/kg, PO) showed a preventive effect against ethanol-induced learning and memory deficit (116).Treatment with crocin (200 µm) on day 7 day after EAE induction, resulted in suppressed XBP-1/s gen in the spinal cord (117).Astrocyte and oligodendrocyte inflammation and cell toxicity are the main causes of EAE, and syncytin-1 and NO produced in this process were reduced by crocin (118).
Pretreatment of traumatic brain injury (TBI) animal model with α-crocin (20 mg/kg) reduced proinflammatory cytokines, microglial activation, and brain edema, and improved neurological severity score in mice (119).Crocin administration (150 mg/kg) resulted in a reduction in the release of calcitonin gene-related peptide (CGRP), as well as an improvement in locomotor function and mechanical behavior in rats with spinal cord contusion injury (120).Moreover, administration of C. sativus (125 and 250 mg/kg) and crocin (50-200 mg/kg, PO) demonstrated protective effects against ethanol-induced performance deficits, such as suppression of LTP, memory disorders, and learning impairments, both in in vitro and in vivo conditions, in a dose-dependent manner (121).
Single dose of C. sativus ethanolic extract (125, 250, and 500 mg/kg, PO) enhanced memory acquisition and retrieval, and improved hippocampal synaptic plasticity in ethanol-induced impairments of learning and memory in animal models.Examination of the rat hippocampal dentate gyrus showed that this effect of crocin occurs via antagonized NMDA receptors changing synaptic potentials (122).Treatment with C. sativus aqueous extract (0.0025-0.56 g/kg), crocin (50 and 200 ml/kg), and safranal (0.2 ml/kg) for 5 days in rats, was able to prevent scopolamineinduced learning impairment (123).C. sativus extract (30 and 60 g/kg) and crocin (15-30 mg/kg) also showed improved retrieval spatial memory and working memory in the novel object recognition test (NORT) and the radial water maze task in rats (98).
Treatment with crocin (15 and 30 mg/kg, IP, for 22 days) on sporadic Alzheimer's disease induced by intracerebroventricular (icv) STZ in male rats has shown improvement in learning and memory performance.A high dose of crocin (30 mg/kg) antagonized the cognitive deficits and diminished the symptoms of the neurodegenerative disease (124).In ethanol-induced memory impairment, crocin blocked the inhibition of NMDA response by ethanol (125).Crocin showed antihyperglycemic, antihypoinsulinemic, and neuroprotective effects in STZinduced diabetic rats (126).
It has been suggested that crocin analogs, including crocetin gentiobiose glucose ester and crocetin di-glucose ester, can reduce the effects of alcohol on LTP blocking (127).Oral administration of crocin (100 mg/kg) in STZ (3 mg/kg, icv)-induced diabetic rats, improved spatial memory deficit and decreased oxidative stress (128).A similar study showed that crocin (15, 30, and 60 mg/kg, IP for 6 weeks) administration to rats with diabetes-induced spatial memory impairment via modulating cerebral oxidative damage modified spatial memory in the Morris Water Maze paradigm (129).
Treatment with crocin (15 and 30 mg/kg), in the form of a single injection, in ketamine-induced rats enhanced recognition memory through antagonized NMDA glutamate receptors indicating its anti-oxidant properties (130).Using the object recognition task and a novel version of the radial water maze, prescribing crocin (30 and 15 mg/ kg) to scopolamine (0.2 mg/kg)-induced performance deficits animal model, modulated storage and/or retrieval of information.Furthermore, the administration of crocins (15 and 30 mg/kg) effectively mitigated the negative effects of delay-dependent recognition memory deficits in normal rats (98).
In rats with ketamine-induced retrograde amnesia, crocin (2 mg/kg, IP) exhibited a correlation with the glutamatergic system in the facilitation of passive avoidance memory, effectively ameliorating retrograde amnesia in rats (131).
Amyloid-β and interferon-gamma (IFN-γ) are major stimulators for oxidant factor production such as NO, intracellular ROS, TNF-α and IL-1β, and NF-κB activation in LPS-induced brain microglial cells.Crocin and crocetin reduced microglial cell activity and oxidant factors and reversed the neurodegeneration process in rats (115).Administration of crocin in different doses during 21 days in Wistar rats led to increased production of proteins and brain factors including CREB and BDNF at higher doses≥50 mg/kg, and nerve growth factor (VGF) in 12.5, 25, and 50 mg/kg doses (135).

Safranal
In Kainic acid induced-anesthetized rats, the extracellular concentrations of glutamate and aspartate in the rat hippocampus were decreased following pretreatment with safranal (72.75 or 291 mg/kg, IP) (138).IP injection of safranal (727.5, 363.75, and 145.5 mg/kg) in the ischemic hippocampus of mice amended reperfusion in global and focal cerebral ischemia by modulating oxidative stress (139).In an experimental animal model of chronic cerebral hyperfusion, safranal at different doses improved spatial cognition through anti-oxidant activity enhancement (133).Administration of safranal (100 mg/kg, IP) after spinal cord injury reduced the inflammatory cytokines and aquaporin-4 expression which alleviated edema (140).Also, safranal (72.75, 145.5, and 291 mg/kg, IP) showed therapeutic effects against neurodegeneration in rats exposed to quinolinic acid (141).Table 5 presents a summary of the neuroprotective effects exhibited by C. sativus and its constituents.

Effect on metabolic disorders C. sativus
It was reported that hydro-methanolic extract of sativus (50 mg/kg, IP) significantly reduced serum glucose and cholesterol levels, and increased insulin levels in healthy male rats (142).Administration of C. sativus ethanolic extract to alloxan-induced diabetic rats in comparison with lbutamide, as a standard drug, reduced fasting blood glucose (FBG) levels by regenerating damaged pancreatic islet cells (143).Administration of C. sativus (40 and 80 mg/kg, for 4 weeks) decreased TC and LDL but increased HDL in type 2 diabetic rats induced by STZ.Furthermore, body weight and serum TNF-α were increased but serum advanced glycation end products (AGEs) level was decreased.Also, blood glucose levels and glycosylated serum proteins were significantly reduced (144).
Peroxisome proliferator-activated receptor  (PPAR) could be activated by fibrates such as C. sativus.Activating these receptors by C. sativus may potentially ameliorate the quantity of PPARα agonists that could potentially contribute to an enhanced lipid profile (145).Administration of aqueous and alcoholic extracts of C. sativus to STZ diabetic rats decreased total glyceride and very low-density lipoprotein (VLDL) but increased adiponectin (146).
Administration of C. sativus extract (200 mg/kg body weight) to STZ-induced diabetic rats five times a week, resulted in the prevention of weight loss and fasting blood sugar.The level of TNF-α was also decreased in the the kidney, liver, and lens tissues of diabetic rats (147).The therapeutic properties of C. sativus in rats with diabetes induced by alloxan resulted in a decrease in FBG and HbA1c levels, as well as an increase in blood insulin levels (148).Treatment with C. sativus ethanolic extract (40 mg/kg) and crocin (80 mg/kg) in rats who received a high-fat diet for 12 weeks improved the lipid profile.Crocin also decreased total glyceride and total cholesterol levels (149).C. sativus increased the synthesis of plasma liver proteins such as albumin through changes in the function of hepatocytes (150).
Administration of C. sativus extract (100 mg/kg) and fenugreek supplementation (1.4 g/kg) to STZ-induced diabetic rats, resulted in a reduction in the levels of total lipids, total cholesterol, triglycerides, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) both in the serum and liver.However, there was an increase in the levels of high-density lipoprotein (HDL) in the serum, as well as an increase in the total protein, serum albumin, globulin contents, and the A/G ratio in the liver.C. sativus, and fenugreek also inhibited the reduction of glycogen and total liver protein and led to the preservation of the structural integrity of the liver (151).In another study, administration of C. sativus ethanolic extract (200,400, and 600 mg/kg) in alloxan-induced diabetic rats significantly decreased blood glucose levels and improved lipid profile (152).Ethanolic extract of C. sativus alleviated ER stress and protein ubiquitination, induced cell apoptosis, and modulated protein oxidation in hepatic I/R injury (153).
C. sativus aqueous extract (200 mg/kg, IP, for 5 weeks) protected the kidney and liver against damage caused by STZ-induced diabetes in rats, due to its anti-inflammatory potential.Also, FBG level was reduced and weight loss was prevented in treated diabetic rats (147).C. sativus ethanolic extract administered to STZ-induced diabetic rats, decreased the levels of aminotransferases, ALT and AST as indicators of the hepatocyte intracellular enzymes, ALP and bilirubin as indicators of liver damage, and albumin as liver protein synthetic function.The plant also improved lipid peroxidation in liver tissue including MDA, GSH, GSH-Px, SOD, and CAT.Therefore, due to the anti-oxidant effects, ethanolic extract of C. sativus showed hepatoprotective effects in STZ-induced diabetic rats with liver injury (154).

Crocin
Crocin (50 or 100 mg/kg, IP, for 150 days) administration in neonatal male Wistar rats with STZ-induced type 2 diabetes, aged 2-5 days, resulted in a decrease in various biochemical factors.These factors include serum glucose, advanced glycation end products, hba1c, triglyceride, total cholesterol, and LDL.Additionally, the level of HDL was increased, and microalbuminuria was reduced in the diabetic model.These changes were utilized in the assessment of the homeostatic model for insulin resistance degrees (156).In the rat model of DZN-induced hepatotoxicity, crocin (12.5 and 25mg/kg/day, IP) inhibited hyperlipidemia through the declined inhibition of ERK performance, and increased LDL receptor expression (157).In a similar animal model, administration of crocin (12.5, 25, and 50 mg/kg/day, IP) reduced caspases, Bax/Bcl-2 ratio, lipid peroxidation, and pathological changes in rat liver, and led to inhibition of hepatotoxicity (158).
The reduction of blood glucose and lipid peroxidation levels, along with the increase in thiobarbituric acid reactive substance (TBARS) and total thiol (SH) group levels, as well as the decrease in anti-oxidant activity in the kidneys and liver, demonstrated the effects of crocin on hyperglycemia and oxidative stress in a rat model of diabetes induced by STZ.These observations provide evidence for the antihyperglycemic and anti-oxidant properties of C. sativus in the diabetic state, which can be attributed to crocin (159).
Crocin ameliorated the toxicity induced by cyclophosphamide through the modulation of the antioxidant status and inflammatory cytokines (160).The impact of crocin and crocetin on the levels of GPX in the liver, SOD in the liver and kidneys, and to a lesser extent on total anti-oxidant capacity (TAOC) in the heart were documented (161).

Crocetin
High-fructose diet (HFD) feeding and crocetin treatment in male Wistar rats reduced free fatty acid, rectified dysregulation of mRNA expression of adiponectin, TNF-α, and leptin which was probably related to alleviated insulin resistance.These observations may suggest the protective effect of crocetin against insulin resistance (162).Administration of crocetin (2 mg/kg, PO) preserved cellular ATP, inhibited mRNA expression and production of TNF-α and IL-1β in hepatocytes, protected against cellular damage, and increased overall survival cell life in hemorrhagic shock (163).
In rats with pancreatic disorder and dexamethasoneinduced insulin resistance, crocetin reduced free fatty acids, triglyceride, and TNF-α, and increased insulin secretion by reinforcing pancreatic islet beta cells (164).Crocetin inhibited insulin resistance and raised hepatic lipoprotein lipase activity in HFD-induced insulin resistance in rats (165).

Safranal
Safranal (0.5 mg/kg/day, IP for one month) administration in 2, 10-, and 20-month-old rats increased the activity of anti-oxidant enzymes and reduced the rate of normal aging by suppressing oxidative stress (166).Safranal decreased serum and pancreas TNF-α and IL-1β, and oxidative stress in HFD and STZ-induced DT2 in rats (167).Administration of safranal (20 mg/kg, PO, for 2 weeks) led to dephosphorylation of the insulin receptor via inhibition of protein tyrosine phosphatase 1B (PTP1B), which plays a role in insulin signaling and improved impaired glucose tolerance (168).In Escherichia colitis, safranal blocked wild-type F1FoATP synthase exclusively.Notably, αR283D mutant ATP synthase experienced a significant reduction of approximately 50% in its functionality (169).Table 6 presents a summary of the effects of C. sativus and its constituents on metabolic syndrome.

Gastrointestinal diseases C. sativus and Crocin
Oral administration of 1% C. sativus aqueous extract in Drosophila melanogaster intestinal immunity, reduced epithelial cell death and ROS production.The antiinflammatory and anti-oxidant effects of C. sativus against intestinal damage led to improved intestinal morphology and increased lifespan of adult flies (170).Administration of aqueous-ethanolic extract of C. sativus (60 mg/ml, IP) reduced ileum contractions in guinea pigs stimulated by electrical field stimulation (EFS).The extract was also able to reduce the ileum contractions induced by epinephrine (1 μM), but it did not affect the contraction induction by KCl (300 mm).These observations showed a postsynaptic inhibition-mediated decrease in intestinal contraction (171).Pre-treatment with oral administration of C. sativus extract, crocin, and safranal, increased glutathione activity and protected gastric tissue against indomethacin-induced tissue changes in diabetic and non-diabetic rats (172).Treatment of mice exposed to indomethacin with both crocin and pantoprazole also reduced gastric index (mm2) (173).

Crocetin
Crocetin administration to 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric adenocarcinoma (AGS) rats inhibited proliferation, induced apoptosis, suppressed Bcl-2, and increased regulation of Bax gene expression as well as increasing lactate dehydrogenase and anti-oxidant agent activity.Together, these effects inhibited tumor growth in a dose-and time-dependent manner.In addition, the observations of the MTT assay showed that treatment of normal human fibroblast (HFSF-PI3) cells with crocetin did not lead to these changes.These results suggest therapeutic applications of crocetin in inhibiting gastric adenocarcinoma in humans (174).
In burn-induced intestinal injury in rats, crocetin (100 and 200 mg/kg) suppressed inflammatory signaling pathways such as NF-κB and polymorphonuclear neutrophil (PMN) accumulation and reduced TNF-α and IL-6 levels.Inhibition of these inflammatory responses led to ameliorating focal necrosis and mucosal ulceration in the damaged small intestine (175).Colonic architecture disorder and diarrhea were the most important disorders that improved after administering crocetin (50 mg/kg, intragastric) to mice.In addition, it reduced the severity of inflammation, lipid peroxidation, NO production, and Th1 and Th2-related cytokines.Therefore crocetin may improve the symptoms of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis including epithelium necrosis, inflammatory cell reduction, and distortion of crypts (49).

Safranal
The reported findings indicate the presence of anti-oxidant, anti-inflammatory, and anti-apoptotic effects of safranal in countering the occurrence of gastric ulcers induced by indomethacin (176).Safranal exerted a suppressive effect on inflammation and apoptosis in indomethacin-induced gastric ulcers, which can be attributed to its ability to inhibit caspase-3.This particular caspase is categorized as one of the cysteine proteinases that participate in inflammatory processes and apoptosis.Anti-secretory and anti-oxidant effects of safranal against gastric ulcers were also reported (177).The activity of Helicobacter pylori was inhibited by the administration of semi-synthetic derivatives of safranal, namely thiosemicarbazonic derivatives and (thiazol-2-yl) hydrazonic, as well as safranal and crocin.These natural components probably inhibit the enzymatic activity of biological processes in H. Pylori strains.These compounds also showed anti-parasitic activity of the plant such as bits effect on Plasmodium and Leishmania (178).The experimental application of N-095, a compound comprising red ginseng, polygala root, saffron, antelope horn, and aloe wood, in rats exhibited a significant safeguarding influence against histamine-induced gastric ulceration (179).Table 7 presents a summary of the gastrointestinal effects exhibited by C. sativus and its constituents.

Respiratory diseases C. sativus
Administration of C. sativus extract with dexamethasone in guinea pigs model of ovalbumin (OVA)-induced asthma increased IFN-γ level, had a stimulatory effect on T-helper 1 cells, and decreased IL-4 production or had an inhibitory effect on T-helper 2 cells leading to improved Th1/Th2 balance (180).The decrease in the count of white blood cells (WBC) and the proportion of neutrophils and eosinophils were observed as a consequence of administration of hydroethanolic extract derived from C. sativus (50, 100, and 200 mg/kg) in sensitized animals in a similar study (181).
Administration of hydroethanolic extract from C. sativus in animals sensitized with OVA resulted in a decrease in lung pathological changes, including infiltration of eosinophils and lymphocytes in the interstitial space, infiltration of cells Table 6.Effects of Crocus sativus and its constituents on metabolic disorders in experimental studies CAT: catalase, DT2: type 2 diabetes ext.: extract, FBG: fasting blood glucose, GPx: glutathione peroxidase, GSTs: glutathione-S-transferase, HDL: high-density lipoprotein, HFD: high-fat diet, I/R: ischemia-reperfusion, iNOS: Inducible nitric oxide synthase, LDL: low-density lipoprotein, PAB: prooxidant-antioxidant balance, PCRCT: placebo-controlled, randomized, clinical trial, SOD: superoxide dismutase, STZ: Streptozotocin, TC: total cholesterol, TG: triacylglycerol, PPAR-α: peroxisome proliferator-activated receptor-α in the interstitium, atelectasis, lung congestion, bleeding, and epithelial damage.Additionally, administration of hydroethanolic extract reduced the total WBC count, as well as the number of eosinophils and lymphocytes, which exhibited a comparable or even more potent effect than that of dexamethasone (182).In a similar study, administration of hydroethanolic extract derived from C. sativus (0.1, 0.2, and 0.4 mg/ ml) to guinea pigs sensitized with OVA resulted in a decrease in serum levels of endotheline-1 (ET-1) and total protein (TP) (183).
Pretreatment with hydroalcoholic extract of C. sativus (50, 100, and 200 mg/kg, IP) in asthmatic rats exhibited a reduction in both the total and differential counts of WBC, red blood cells (RBC), and platelets, indicating that the plant can be used in the treatment of asthma (181).Administration of ethanolic extract of C. sativus stigma (100-800 mg/kg, IP), safranal (0.25-0.75 ml/kg, IP.), and crocin reduced the number of citric acid 20%-induced cough in guinea pigs (184).The relaxant effect of C. sativus (0.1 and 0.2 g%) and safranal (1.25 and 2.5 mg) on tracheal smooth muscles (TSM) by stimulation of β2-adrenoreceptors and inhibition of histamine (H 1 ) receptors was also demonstrated (185).Hydro-ethanolic extract of C. sativus (0.15, 0.3, 0.45, and 0.60 g%) showed a relaxant effect on guinea pigs TSM in a dose-dependent manner similar to the effect of theophylline (186).It was shown that the relaxant effect of the extract of saffron on the tracheal smooth muscle of guinea pigs is mediated through a stimulatory effect on β2adrenoreceptorsor inhibitory effect on histamine (H 1 ) or muscarinic receptors (187,188).
Treatment of OVA-sensitized mice with crocin (100 mg/ kg), significantly reduced the BALF levels of IL-4, IL-5, and IL-13, inhibited the expression of lung eotaxin, p-JNK and p-ERK genes, lung eosinophil peroxidase, and decreased airway hyperreactivity indicating its anti-asthmatic property (190).Administration of crocin (25 mg/kg/day, PO) in mice with asthma induced by OVA resulted in a decrease in levels of TNF-α, IL-4, IL-13, LDH, and MDA, while levels of SOD and GSH in lung tissue were increased (191).
Administration of crocin (50 mg/kg/day, 3 times/week, for 8 weeks) to cigarette-induced COPD rats inhibited the gene expression and protein production of a nuclear factor erythroid 2-related factor 2 (Nrf2), protein kinase C (PKC), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and glutamatecysteine ligase catalytic (gclc), and prevented lung damage by strengthening the anti-oxidant system (192).Also, oral administration of crocin (50 mg/kg) improved acute lung damage caused by intratracheal injection of LPS by suppressing myeloperoxidase (MPO) activity, preventing lung edema, reducing NO level and iNOS expression, and inhibiting the production of TNF-α and IL-1β (193).Treatment of LPS-induced lung injury in mice with crocin (50 and 100 mg/kg) resulted in the suppression of phosphoiκb expression and the activity of the NF-κB pathway.Furthermore, crocin treatment led to a decrease in the expressions of TNF-α and IL-6 at the protein and mRNA levels, as well as a reduction in the levels of macrophage chemoattractant protein-1 (MCP-1) in the lung tissue (194).

Crocetin
Intranasal administration of crocetin (100 μM/day, for 9-10 weeks) in OVA-induced asthma in mice, reduced the number of Treg cells and the levels of Foxp3 and TIPE2, indicating treatment properties of crocetin in asthma (195).
Administration of crocetin (100 mg/kg, IV) and a trans isomer of sodium crocetinate (TSC) in rats with hypoxic exercise, increased the ability of the lung for O2 diffusion and transport in animal models (196).

Safranal
Safranal, administered at varying doses of 0.15, 0.30, 0.45, and 0.60 ml of a solution containing 0.2 mg/ml, exhibited a dose-dependent relaxant effect on the tracheal smooth muscle of guinea pigs, resembling the effect observed with theophylline (186).Administration of safranal (1.25, and 2.5 μg/ml) on guinea pig TSM showed similar effects to chlorpheniramine which indicated an inhibitory effect on histamine H 1 receptors as a competitive antagonist (198).Studies have shown that the possible mechanisms of safranal (1.25 and 2.5 mg) induced relaxation of TSM include stimulation of β2-adrenoreceptors and inhibition of histamine (H 1 ) receptors (198,199).Furthermore, the cumulative log concentration-response curves of methacholine acquired while the aqueous-ethanolic extract of C. sativus (25,50, and 100 µg/ml) and safranal (0.63-2.5 µg/ml) were present at various concentrations exhibited a noticeable deviation to the right when compared to the methacholine curves generated in the presence of saline.Consequently, these findings clearly suggest the existence of a competitive antagonistic influence exerted by safranal on muscarinic receptors (199).
Safranal decreased TSM responsiveness to methacholine in sensitized guinea pigs through increased IFN-γ and decreased IL-4 and NO levels (200).
Safranal significantly improved the pathological and immunological changes of the lungs and alleviated lung pathological changes.It also reduced serum histamine levels and improved total and differential WBC counts in lung lavage in OVA-sensitized guinea pigs (182).

Kaempferol
Oral administration of kaempferol to OVA-sensitized mice, inhibited mucus secretion in bronchial airways cells and suppressed goblet cell hyperplasia (203).Table 8 presents a summary of the respiratory effects exhibited by C. sativus and its constituents.

Renal diseases C. sativus
The diuretic property of C. sativus was shown by increasing blood flow and improving blood circulation (11).In addition, in the realm of diagnosing and treating conditions affecting the glomerulus such as glomerulonephritis or localization of antigen-antibody complexes, C. sativus as a safe remedy showed a diuretic effect by increasing renal blood flow (204).In a descriptive study in cats, an aqueous extract of C. sativus showed a diuretic effect and increased glomerular filtration rate (205).Treatment with C. sativus petal extracts (40 mg/kg, IP) of gentamicin sulfate-induced nephrotoxicity in male Wistar rats-induced kidney failure, resulted in a significant reduction in serum BUN and creatinine levels, as well as improving kidney histological changes, indicating a protective effect of C. sativus against kidney failure caused by gentamicin sulfate (206).
Administration of C. sativus (10, 40, and 90 mg/kg) increased artery blood flow velocity in kidney arterials due to the lowest dose of C. sativus (10 mg/kg) in male Sprague-Dawley rats.It also directly affected endothelial cells and improved their function.While the use of low doses of the plant is recommended as a treatment for ischemic kidneys, higher doses were harmful due to tissue lesions such as acute tubular necrosis or injury (ATN) and glomerulopathy (204).Treatment with hydro-ethanolic extract of C. sativus petals (20 mg/kg) in acetaminophen (APAP)-induced acute nephrotoxicity in male Wistar rats significantly decreased serum creatinine and uric acid.These results indicated a protective effect of C. sativus on acute nephrotoxicity induced by APAP (207).Treatment with C. sativus extract (5, 10, or 20 mg/kg, IP) in male rats with renal inflammation induced by I/R was observed to significantly decrease the levels of MDA and TNF-α, infiltrated leukocytes, as well as the serum concentrations of creatinine and urea-nitrogen.Additionally, the expression levels of intercellular adhesion molecule-1 (ICAM-1) mRNA were down-regulated.This study showed that C. sativus can protect the kidney against I/R-induced AKI due to its anti-inflammatory and antioxidant effects (208).
Administration of hydro-ethanolic extract of C. sativus (for 4 weeks, IP) to middle aged and aged rats, significantly reduced pro-inflammatory cytokine, lipid peroxidation, and oxidant factors, and suppressed inflammatory gene expression in aging rats' kidneys (209).Administration of C. sativus aqueous extract and crocin significantly diminished the oxidative stress caused by renal I/R in rats (210).

Crocin
In STZ-induced diabetic male rats, treatment with crocin for two months, lowered blood glucose levels, increased insulin secretion, and improved renal function.In addition, treatment with crocin increased creatinine clearance with proteinuria along with a decrease in serum creatinine and nitrogen levels.It also reduced the content of NOS and LDH activity.Oxidative indices such as MDA and toll-like receptors 4 and IL-6 were decreased and protein expression of NF-κB/p65 was inhibited, but serum anti-oxidants such as SOD, GSH, and CAT were significantly increased (211).Table 9 presents a summary of the renal effects exhibited by C. sativus and its constituents.

Urogenital diseases C. sativus
Administration of C. sativus extract along with Serenoa repens (Serenoa) and Pinus massoniana (Pinus) reduced inflammation in bacterial or non-bacterial prostatitis and improved its symptoms, including sexual dysfunction such as concomitant erectile dysfunction and urinary tract disorder.The production of ROS in immortalized prostate cells (PC3) was inhibited in LPS-induced prostatitis, and the NFκb and PGE2 pathways were suppressed.The results showed that the combination of C. sativus with two other compounds has synergistic anti-inflammatory and antioxidant effects in prostatic treatment (212).
Treatment of cadmium-induced infertility and impaired spermatogenesis with C. sativus in rats decreased cell division and lipid peroxidation, and increased cell proliferation and Johnsen scores in seminiferous tubules, free serum testosterone, and the number and survival time of sperm in the cauda epididymis (213).

Crocin
Increased ROS production levels negatively affected the genetic integrity, motility, and fertilization capacity of sperm.Treatment of bovine sperm with crocin (0.5, 1, and 2 mM at intervals of 2-4 hours) significantly reduced ROS production and lipid peroxidation and increased motility and viability.In addition, the number of fragmented cells was decreased.These results indicate increasing fertilization capability of crocin in bovine sperm by modulating the concentration of DNA (215).
In an experimental animal study, simultaneously, on male Sprague Dawley rats that received cyclophosphamide (15 mg/kg, once a week for 8 weeks) for induction of toxicity in testicular tissue, administration of crocin (10 and 20 mg/kg/ day, for 56 days) improved glutathione redox cycle protection and sperm quality, increased hormonal mediators, and reduced caspase-3 activity and the process of apoptosis in testicular tissue.These data suggested the protective effect of crocin on testicular tissue and function against the side effects of cyclophosphamide in a dose-dependent manner (216).Table 9 presents a summary of the urogenital effects exhibited by C. sativus and its constituents.

Discussion
There are various hypotheses to explain the anti-tumor properties of C. sativus and its main components, the most important of which include the inhibitory effect on DNA and RNA synthesis without an inhibitory effect on proteins, and the inhibitory effect on chain reactions that eventually lead to free radical production, deactivate topoisomerase II with carotenoids, and natural metabolic functions such as conversion carotenoids to retinoids (1).It is explained that C. sativus can be used as an anti-cancer agent by the following mechanisms: inhibition of the cell cycle by targeting the DNA sequence and modulating gene expression, which leads to cessation of cell proliferation in the early stages and activation of apoptosis, which leads to the death of cancer cells.C. sativus has a protective effect on cancer through induction of apoptosis, inhibition of cell proliferation, and inflammatory and anti-oxidant activities (31).C. sativus also plays an important role in preventing tumor progression by regulating some genes, such as p53, prb, Bcl-2 family, and their protein products, which play a key role in cell division and apoptosis.Crocin induces apoptosis, reduces cell invasion, migration, and adhesion by up-regulating e-cadherin expression, and has antimetastatic potential.Crocetin inhibits proliferation cells by inhibiting glycoprotein and polyamine synthesis, modulates oxidant/anti-oxidant balance, down-regulates the proinflammatory cytokines, and inhibits cyclooxygenase-2 (COX-2) expression in cancer cells (1).Safranal by inhibiting proliferation and apoptosis induction in cancer cells, can be used as a natural treatment for cancer, especially colorectal cancer (217).C. Sativus can be used to treat patients who suffer from hypertension through a reduction in heart rate and contractility via Ca 2+ channel blockage (54).C. Sativus probably reduces the incidence of ventricular arrhythmia by reducing electrical conductivity, prolonging APD, and reducing sensitivity (55).C. sativus through stimulation and production of NO leads to the strengthening of the protective function of the AV node against supraventricular arrhythmia (57).C. sativus through the anti-oxidant property, showed a protective effect against myocardial I/R injuries (53).Crocin also showed a protective effect on arrhythmias caused by ischemic heart disease (60) and showed prevention of heart disease due to strengthening the anti-oxidant defense system (61).Crocetin possesses the potential to serve as a pharmacological agent in the clinical setting for the management of hypertrophy (74).Furthermore, it exerts an influence on atherosclerosis using its anti-oxidant activity, as well as through its capacity to inhibit the inflammatory response and the p38 MAPK signaling pathway (65).The anti-inflammatory and antioxidant characteristics of crocetin may exhibit a safeguarding influence over injuries associated with myocardial I/R (71).Safranal has been demonstrated to diminish MSBP (58) and exhibited a protective effect on myocardial I/R injuries using heightened phosphorylation of Akt/GSK-3β/eNOS, curbed expressions of IKK-β/NF-κB proteins, and potential that counteracts apoptosis (78).
Various studies have proven the antidepressant, antianxiety, and anti-seizure effects of C. sativus (leaves and stigma) and its major components.Although the mechanistic pathway of the anti-anxiety effect of C. sativus and its derivatives has not yet been determined, studies suggest that the flavonoids present in C. sativus interact at the benzodiazepine site in the GABA-A receptor which may lead to anti-anxiety effects.Based on in vitro and in vivo studies, C. sativus and its constituents showed antiinflammatory, anti-oxidant, and neuroprotective activities.These properties are due to the interaction with GABA, cholinergic, glutamatergic, and dopaminergic systems and can be a strategic treatment in neurological disorders such as Alzheimer's.The proposed mechanisms for anti-Alzheimer's properties of crocin are inhibition of neurons in the hippocampus via antagonizing NMDA receptor, and the production, accumulation, and formation of amyloid plaques (125).C. sativus and its constituents can reduce ethanol, scopolamine, ketamine, morphine, and apomorphineinduced memory acquisition and learning impairment.The plant antagonizes different causes of memory impairment and other neurodegenerative disorders including lipids, proteins, and nucleic acids degradation due to decreased oxidant agents in neurotransmitters/neurotrophin systems (218,219).C. sativus can be also used in the treatment of multiple sclerosis due to its anti-oxidant properties (90).The constituents of C. sativus, namely crocin and crocetin, offer neuroprotection through the reduction of various neurotoxic molecules produced by activated microglia (115).Consequently, there has been consideration of negative regulators of microglial activation as potential therapeutic candidates for addressing neurodegenerative conditions, exemplified by Alzheimer's and Parkinson's diseases (115).
C. sativus showed protective effects on the liver suggesting its potential role in the treatment of liver disorders (220).C. sativus can be considered a protective agent in the liver and kidneys against inflammatory processes caused by hyperglycemia (147).C. sativus supplements and their active ingredients such as crocin can be used as a therapeutic strategy in the treatment of fatty liver in HFDinduced obese rats.Possible mechanisms of biochemical and histopathological treatment include liver enzyme modulation and restricted fatty infiltration in hepatocytes leading to the liver returning to normal size (221).Crocin may be considered a novel protective agent in hyperlipemia through modulating of ERK pathway and increase of LDL receptor expression (157).The anorectic and anti-obesity properties of C. sativus and crocin can be used clinically in the prevention and treatment of obesity (155).C. sativus can increase the level of insulin secretion from pancreatic beta cells and can be considered in the treatment of diabetes in the future (142).Due to the anti-oxidant effects, C. sativus showed hepatoprotective effects in diabetic rats with liver injury (154).The findings showed that anti-hyperglycemic and anti-oxidant properties of C. sativus in diabetic patients are due to crocin (159).The radical scavenging activity of active constituents of C. sativus, such as crocin and safranal showed the highest anti-oxidant activity of crocin at concentrations of 500 and 1000 ppm in ethanol solution of 48 to 64%, respectively.However, at the same concentrations, safranal showed lower radical scavenging activity.Therefore, the anti-oxidant properties of C. sativus are related to the synergistic effect of crocin and safranal but are mainly due to crocin (222).
Various studies have shown the potential therapeutic effects of C. sativus and its constituents such as crocin on a wide range of digestive disorders such as ulcerative colitis, gastrointestinal cancer, and peptic ulcer (5).C. sativus affects digestive disorders due to its anti-oxidant and smooth muscle relaxant properties (171,172).Crocin is converted to crocetin by hydrolysis and then can be converted to mono-and di-glucuronide conjugate metabolites after absorption by the intestine (149).Percentage uptake of crocin in different parts of the gastrointestinal tract was reported as 13.81% in the duodenum, 9.89% in the jejunum, 10.07% in the ileum, and 10.04% in the colon.Also, the degradation of crocin in these parts was 13.01%, 10.11%, 9.95%, and 10.45%, respectively.The aforementioned findings substantiated that crocin does not possess the complete capability to be assimilated across the entirety of the gastrointestinal tract (223).After oral administration, crocin is not present or accumulates in plasma, and its hydrolyzed metabolite is absorbed into the blood as crocetin and is excreted predominantly in the intestine (224).Oral administration of crocetin, its crocetin-monoglucuronide, and crocetin-diglucuronide exist in free and intact forms in plasma.However, no glycoside forms of crocin were found in the blood (225).It was shown that the pharmacokinetic properties of crocin in vivo are mainly related to crocetin (226).The therapeutic applications of crocetin were suggested for inhibiting gastric adenocarcinoma in humans (174).
The therapeutic properties of C. sativus and its constituents have been known since ancient times and have been further supported by modern pharmacological research.These effects have been observed in the context of lung diseases, specifically in terms of antitussive properties (184), relaxation of the tracheal smooth muscle, stimulation of β2-adrenoceptors, inhibition of histamine (H1) receptors in the tracheal smooth muscle (185,227), as well as antiinflammatory and immunomodulatory activities (4).This suggests that C. sativus and its constituents may have potential therapeutic applications in the treatment of lung diseases.The effects of C. sativus and its compounds on asthma and chronic pulmonary diseases (COPD) were also reported (228).C. sativus and its derivatives can be used as antitussive effect agents probably due to airway dilation property (184).The TSM relaxant effects of C. sativus and safranal are probably mediated by stimulation of β2-adrenoreceptors and inhibition of histamine (H 1 ) and muscarinic receptors (185,199).The suppressive properties of C. sativus on inflammation are likely facilitated through the reduction of inflammatory cytokines as well as the overall and distinct counts of WBC within the lung (182).C. sativus has been observed to diminish the levels of IL-4 while concurrently augmenting the secretion of IFN-γ and the IFN-γ/IL-4 ratio, thereby indicating its influence on the balance between Th1 and Th2 (200,202).Crocin strengthens the anti-oxidant system (192), crocetin inhibits Treg cells, Foxp3, and TIPE2 (195), and kaempferol inhibits the effect on mucus secretion in bronchial airway cells and goblet cell hyperplasia (203) which could affect asthma treatment.
The diuretic property of C. sativus was shown by increasing blood flow and improving blood circulation (11).In addition, in the treatment of glomerulus diseases such as glomerulonephritis or localization of antigen-antibody complexes, C. sativus as a safe remedy showed a diuretic effect by increasing renal blood flow (204).C. sativus indirectly improves the function of the cardiovascular system by strengthening vascular blood flow (204).The findings indicated the protective effect of C. sativus against kidney failure caused by gentamicin sulfate (206) and acute nephrotoxicity induced by APAP (207).C. sativus possesses the capability to safeguard the kidney from I/R-induced AKI by its anti-inflammatory and anti-oxidant properties (208).In addition, crocin inhibits the process of fibrosis in kidney tissue by inflammatory and fibrotic cascade activation as well as free radical scavenging and anti-oxidant defense system boosting (211).

Conclusion
The findings of multiple experimental studies have demonstrated that C. sativus and its primary constituents, including crocin, crocetin, and safranal, possess significant potential in the treatment of a wide spectrum of diseases.This comprehensive review aims to provide an overview of the pharmacological effects of C. sativus and its main constituents in both traditional and modern medicine.Notably, the plant and its derivatives have been reported to exhibit preventive or therapeutic effects against cancer, as well as the treatment of various disorders such as cardiovascular, central nervous system, metabolic, gastrointestinal, respiratory, renal, and urogenital disorders.Furthermore, the anti-proliferative, anti-genotoxic, apoptogenic, chemoprotective, and cytotoxic effects of C. sativus on various types of cancer have been demonstrated.
In the realm of the cardiovascular system, C. sativus and its constituents exhibit an ameliorative impact on cardiac hemodynamic function.Furthermore, they succeed in reducing blood pressure and I/R damage in the ischemic region using modulating beta and alpha receptors, as well as possessing anti-inflammatory and anti-oxidant properties.
The therapeutic effects of C. sativus and its components extend to neurodegenerative diseases, such as Alzheimer's and Parkinson's.This is achieved through the suppression of pro-inflammatory gene expression and the inhibition of inflammatory mediators in microglia cells.
By acting upon β2 adrenergic, muscarinic, and histamine receptors, the plant and its derivatives induce relaxation in the airways.Additionally, the plant exhibits a preventive effect on inflammatory lung disorders owing to its antiinflammatory, immunomodulatory, and anti-oxidant properties.
Through the effect on histamine receptors in the stomach, C. sativus and its component reduce acid secretion and help to improve the mucosal defense layer.The plant and its derivatives also modulate the effects of menopause and premenstrual syndrome in women and prostate disorders in men, strengthen the anti-oxidant defense system, and reduce the disease process.
A multitude of studies have been conducted to investigate the impact of C. sativus and its constituents on various disorders using both in vivo and in vitro laboratory animal models.While these investigations are essential, they are not sufficient, and further clinical trials are imperative to explore the unknown aspects of the therapeutic effects of C. sativus and its primary constituents on diverse disorders.
Pharmacological effects of Crocus sativousSaadat et al.
Pharmacological effects of Crocus sativousSaadat et al.
Pharmacological effects of Crocus sativousSaadat et al.
Pharmacological effects of Crocus sativousSaadat et al.

Table 1 .
Traditional uses of Crocus sativus in ancient times Pharmacological effects of Crocus sativous Saadat et al.

Table 2 .
Major components of Crocus sativus Figure 1.Chemical structure of chemical constituents of Crocus sativus

Table 5 .
Neuroprotective effects of Crocus sativus and its constituents in experimental studies Iran J Basic Med Sci, 2024, Vol. 27, No. 4 Saadat et al.Pharmacological effects of Crocus sativous 400 the neuroprotective effects exhibited by C. sativus and its constituents.